Non classical risk factors for gestational diabetes
mellitus: a systematic review of the literature
Fatores de risco não clássicos para diabetes
mellitus gestacional: uma revisão
sistemática da literatura
1 Programa de Pós-graduação em Epidemiologia, Universidade Federal de Pelotas, Pelotas, Brasil. Correspondence M. A. S. O. Dode
Programa de Pós-graduação em Epidemiologia, Universidade Federal de Pelotas.
Av. Anchieta 2023, apto. 801, Pelotas, RS
96015420, Brasil. malicedode@terra.com.br
Maria Alice Souza de Oliveira Dode 1
Iná S. dos Santos 1
Abstract
Age, obesity and family history of diabetes are well known risk factors for gestational diabetes mellitus. Others are more controversial. The ob-jective of this review is to find evidence in the lit-erature that justifies the inclusion of these other conditions among risk factors. The MEDLINE, Cochrane, LILACS and Pan American Health Organization databases were searched, cover-ing articles datcover-ing from between 1992 and 2006. Keywords were used in combination (AND) with gestational diabetes mellitus separately and with each one of the risk factors studied. The meth-odological quality of the studies included was assessed, resulting in the selection of 41 papers. Most studies investigating maternal history of low birth weight, low stature, and low level of physical activity have found positive associa-tions with gestational diabetes mellitus. Low so-cioeconomic levels, smoking during pregnancy, high parity, belonging to minority groups, and excessive weight gain during pregnancy present-ed conflicting results. Publication bias cannot be ruled out. Standardization of techniques, cutoff points for screening and diagnosis, as well as studies involving larger sample sizes would al-low future meta-analyses.
Gestational Diabetes; Diabetes Mellitus; Risk Factors
Introduction
Gestational diabetes mellitus is a heterogeneous disorder characterized by intolerance to carbo-hydrates and hyperglycemia in varied degrees of intensity, with onset or first diagnosis during pregnancy 1. The pregnancy is a physiological
situation of insulin resistance; therefore, it may be the first moment in a woman’s life to test her capacity to respond to a physiological stress and to detect those at greater risk of developing dia-betes in the future.
Several international guidelines 2,3,4,5,6
rec-ommend selective screening for pregnant wom-en older than 29 or for younger womwom-en with risk factors. Others advise universal screening 7. In
Brazil, the Ministry of Health and the Work Group in Diabetes and Pregnancy (Grupo de Trabalho em Diabetes e Gravidez – GTDG) recommend that all pregnant women should be screened for gestational diabetes mellitus (through fasting glucose in the 20th week of gestation) and, in the
presence of risk factors and regardless of the first result, that screening should be repeated in the third trimester 7,8.
gesta-The goal of this review is to evaluate the re-cent literature in order to establish whether all women presenting these conditions should be screened for gestational diabetes mellitus.
Methods
The search was made in the MEDLINE database and studies from between 1992 and 2006 were included. The keywords used in the search were the combination (AND) of gestational diabetes or pregnancy diabetes with each one of the fol-lowing terms (in parenthesis are, respectively, the number of titles found with each one of the asso-ciation, before eliminating the duplicates): birth weight (1,868; 2,847); low birth weight (798; 519); low birth size (45; 85); small birth size (53; 63); small for gestational age (525; 376); age (1,154; 2,860); obesity (335; 923); cigarette smoking (17; 45); weight increase (291; 451); weight gain (271; 374); body mass index (560; 738); height (165; 232); short stature (28; 25); anthropometry (437; 584); race (268; 380); ethnics (308; 404); family history of diabetes (199; 272); education (217; 426); eco-nomic level (12; 21); social and ecoeco-nomic factors (14; 15); physical activity (97; 150); exercise (135; 226); and risk factors (1,365; 2,319) . The terms age, obesity and family history of diabetes melli-tus were included in an attempt to identify other risk factors of interest for the current review.
After searching, 5,759 titles were indentified. The first selection was made through the reading of the titles. Criteria for article inclusion were: English, Portuguese, Spanish or French language; studies involving humans; and papers that evalu-ated gestational diabetes mellitus as an outcome and risk factors for its development. From the remaining 357 abstracts, 41 papers were selected. These selected papers studied one or more of the chosen risk factors and included gestational dia-betes mellitus as outcome. Studies with animals and those that evaluated treatments for gesta-tional diabetes mellitus were excluded.
The methodological quality of the selected papers was evaluated using the criteria suggested by Downs & Black 9. This is a checklist developed
to assess the methodological quality not only of randomized controlled trials but also non-ran-domized studies. Using the criteria, it was pos-sible to construct a profile of the paper, highlight-ing its methodological strengths and weaknesses. This checklist consisted of 27 items distributed across five sub-scales:
(1) Reporting (10 items): which assess wheth-er the information provided in the papwheth-er was suf-ficient to allow a reader to make an unbiased as-sessment of the findings of the study;
(2) External validity (3 items): which reviews the extent to which the findings from the study could be generalized to the population from which the study subjects were derived;
(3) Bias (7 items): which address biases in the measurement of the intervention/exposition and the outcome;
(4) Confounding (6 items): which address bias in the selection of study subjects;
(5) Power (1 item): which attempts to assess if negative findings from a study could be due to chance.
In items 4, 14, and 15, “intervention” was interpreted as “exposure,” and in no. 19
“com-pliance with the intervention” was replaced by “avoidance of misclassification error of the ex-posure”. Items 8, 13, 23, and 24 were not con-sidered, since these are specific to clinical trials. Answers were scored 0 or 1, therefore, the highest score could be 23. The scores given to each paper and commentaries are shown in the Table 1. For each of the exposures, a funnel plot was drawn to evaluate publication bias. Because of the lim-ited number of available studies in the literature for some of the exposures, it was only possible to plot the following: weight of the mother at birth, height and Asian ethnicity and Indian/Pakistani ethnicity.
Results and discussion
Table 1 presents alphabetically (by author) a summary of the studies included in the review. The methodological quality of studies ranged from 10 to 22 (median 18; SD = 2.9). The quality of reporting was good. Most of the studies (80%), however, lack information on representative-ness. With regard to internal validity (items 14 to 27) the main weaknesses identified were lack of information on the methodology used for defin-ing the outcome and adjustment for confound-ing. In addition, none of the studies presented information if the power was enough to detect the association between exposure and gesta-tional diabetes mellitus; and characteristics of losses and refusals were neither presented nor discussed. The sections below present a summa-ry of the publications on each of the potential risk factors and a discussion on methodological issues.
Birth weight
Since the fetal origin theory began to be dis-cussed 10, stating that susceptibility to chronic
associa-Table 1
Review table: risk factors for gestational diabetes mellitus.
Authors (place/year) Design n Data source Gestational time Gram glucose/ time diagnostic criteria Risk factors investigated Main results Prevalence/Association with gestational diabetes mellitus
Score/Comments
Anastasiou et al.
26 (Greece/1998)
Cross-sectional 2,772 Primary 24-32 weeks 100g/3hs NDDG
Age, education, weight; prior and current BMI, height, born before/after
1960 (war)
Prevalence: 24.7% Average height inversely associated to increased glucose
intolerance; adjustment for weight, education separately
Score: 13 Study center reference. Regression
used height as outcome; gestational
diabetes mellitus as predictor
Berkowitz et al. 35
(USA/1992) Cohort 10,187 Secondary 26-32 weeks 100g/3hs NDDG Age, race/ethnicity, birth place, marital status, health insurance,
hospital, parity, prior preterm birth, stillbirth, prior BMI, family history of diabetes mellitus, smoking habits, drugs
Prevalence: 3.2% Adjusted association: > age, eastern race, fi rst generation Hispanic, other race/ethnic
groups, public service, > prior weight, family history of diabetes mellitus > gestational
diabetes mellitus risk
Score: 19 Public hospital screened more than
private hospital
Bo et al. 75
(Italy/2002) Case-control 700 Primary 24-28 weeks 100g/3hs Carpenter & Coustan
Age, education, job, prior and current BMI,
height, parity, family history of gestational diabetes mellitus, previous pregnancy
Adjusted association: < education, manual worker,
owner primary home + education > gestational diabetes mellitus risk
Letter to editor without evaluation
Bo et al. 24
(Italy/2003) Case-control 300 Primary/Secondary 24-28 weeks 100g/3hs Carpenter & Coustan
Birth weight, gestational age, family history of diabetes mellitus, age,
prior, current weight, height, BMI, weight gain, smoking habits
Adjusted association: < birth weight > gestational diabetes
mellitus risk
Score: 18 Weight in quartiles and means differences
evaluated
Branchtein et al. 27
(Brazil/2000) Cross-sectional 4,973 Primary 21-28 weeks 75g/2hs WHO
Age, color, education, weight, prior BMI, height, skin-fold, waist
circumference, family history of diabetes mellitus, parity, clinic,
gestational age, gestational diabetes
mellitus prior, room temperature
Adjusted association: height ≤ 151cm > gestational diabetes mellitus risk (after stratifi cation for global adiposity, association
signifi cant only for obese)
Score: 17 Interaction height vs. weight non evaluated
Corrado et al. 62
(Italy/2006) Cohort 2,922 Secondary Oral test of glucose tolerance Carpenter & Coustan
Age, BMI, family history of diabetes mellitus,
weight gain
Prevalence: 2.9% Adjusted association: > age, > BMI, family history of diabetes mellitus > gestational diabetes
mellitus risk
Letter to editor without evaluation
Deruelle et al. 63
(France/2004) Case-control 348 Primary 50g/1h DIAGEST O’Sullivan
Age, height, weight, smoking habits, socioeconomic level,
hypertension
Weight gain > 18kg not associated with > gestational
diabetes mellitus risk
Score: 11 Cases and controls
selected by exposition; weight gain measured at the end of pregnancy; no
adjustments
Dempsey et al. 71
(USA/2004) Case-control 541 Primary/secondary 24-28 weeks 100g/3hs NDDG
Age, parity, education, social-economic level, prior BMI, physical
activity
Physical activity previous year: 55% reduction in gestational diabetes mellitus risk; physical activity fi rst 20 weeks compared
with inactive: 48% reduction in gestational diabetes
mellitus risk
Score: 21 Physical activity self
reported
Dempsey et al. 72 (USA/2004) Cohort 909 Primary 24-28 weeks 100g/3hs NDDG
Age, education, income, job, smoking habits, alcohol, height, prior weight, medical history,
parity, physical activity year before and previous
week
Incidence: 4.6% Adjusted association: reduced
risk any physical activity, previous year and during pregnancy < gestational diabetes mellitus risk
Score: 19 Sample selected two
clinics
Di Cianni et al. 33
(Italy/2003) Cohort 3,806 Primary 24-28 weeks 100g/3hs Carpenter & Coustan
Age, weight; prior BMI, weight gain, height, family history of diabetes mellitus, obstetric history
Prevalence: 8.74% Association:> age, > BMI prior, < height, > weight gain, family history of diabetes mellitus < gestational diabetes mellitus risk
Score: 19 Risk not shown
Dye et al. 70
(USA/1997)
Cohort 12,799 Primary/secondary
Medical record Age, race, parity, prior BMI, weight gain, health
insurance
Prevalence: 2.9% Stratifi cation by BMI: BMI > 33kg/m2 > physical activity < gestational diabetes mellitus risk; BMI > 33kg/m2 + private insurance + reduced physical activity: > gestational diabetes
mellitus risk
Score: 17 Self-reported physical
activity; interaction insurance vs. physical activity not evaluated
England et al. 43
(USA/2004) Cohort 3,774 Primary 13-21 weeks 100g/3hs O’Sullivan
Smoking habits Adjusted association: > smoking at study enrollment (13-21 weeks) > gestational diabetes
mellitus risk
Score: 17 The design of the study was not for this
evaluation
Egeland et al. 20
(Norway/2000)
Cohort 138,714 Secondary
Self-reported Birth weight, ponderal index, weight/gestational
age, grandmother characteristics during her
pregnancy (age, parity)
Prevalence: 0.36% Adjusted association: > age,
> parity, low birth weight, < weight/gestational age > gestational diabetes mellitus
Score: 21 Self-reported gestational diabetes
mellitus
Innes et al. 21
(USA/2002)
Cohort 23,395 Secondary
Medical record ICD 9th revision
Uterus experiences (multi fetal, birth order, parents education, age, illnesses and childbirth
mother); birth weight, gestational age, race/
ethnic, age, marital status, job, education,
insurance, programs welfare, prenatal, alcohol, smoking habits, height, BMI, weight gain
Prevalence: 1.9% Adjusted association: > age, < education, > BMI,< height, low birth weight, family history of diabetes mellitus > gestational
diabetes mellitus risk
Score: 22 Data from 2 big datasets of New York
state (USA)
Jang et al. 25
(Korea/1998) Cross-sectional 9,005 Primary 24-28 weeks universal 100g/3hs NDDG
Age, weight, BMI, height; family history of diabetes mellitus, parity,
weight gain
Prevalence: 1.9% Adjusted association: > age, > BMI, family history of diabetes mellitus, < height, weight gain > gestational diabetes mellitus risk
Score: 20 Universal screening
Keshavarz et al. 30
(Iran/2005) Cohort 1,310 Primary 24-28 weeks universal 100g/3hs Carpenter & Coustan
Age, social economic level, job, height, BMI, parity, family history of
diabetes mellitus
Incidence: 4.8% Association: > age, > parity, < height, family history of diabetes
mellitus, BMI, lower economic status > gestational diabetes
mellitus risk
Score: 14 One hospital/no
adjustments
Kieffer et al. 48
(USA/1999)
Cross-sectional 10,854,224
Secondary
Self-reported Age, education, parity, marital status, prenatal,
race/ethnic
Prevalence: 2.5% Adjusted association:
Asian-Indians, black people, Philippine, Puerto Ricans, South
and Center American born outside USA > gestational diabetes mellitus risk compared
to white
Score: 18 Self-reported gestational diabetes
mellitus Table 1 (continued)
(continues)
Authors
(place/year) Designn Data source Gestational time Gram glucose/ time diagnostic criteria Risk factors
investigated Prevalence/Association with Main results gestational diabetes mellitus
Khine et al. 52
(USA/1999)
Case-control/Cohort 632/11,486
Secondary
Medical record ICD 9th revision
Age, race/ethnicity, weight, height, BMI, family history of diabetes
mellitus, medical disorders (gestational
diabetes mellitus, macrossomy, stillbirth,
anomalous embryo), health insurance
Teenage pregnancy: incidence: 1.7% (> BMI total > gestational
diabetes mellitus risk) Total population: incidence: 4.8% (> Asiatic, > age, > BMI, > gestational diabetes mellitus
risk)
Score: 19 Case-control/Cohort
Kousta et al. 32
(UK/2000)
Case-control 816 Primary/secondary
Medical record Oral test of glucose tolerance/WHO
Height, ethnicity, age Average height for European, South Asians, Afro-Caribbean with gestational diabetes
mellitus < controls
Score: 16 Cases: 10 hospitals
in London and neighborhood/ Controls: 1 hospital
No adjustments
Kumari et al. 45 (Arab
Emirates/2002)
Case-control 4,721 Secondary
Medical record Age, previous morbid (anemia, hypertension,
eclampsy)
> Parity > Incidence gestational diabetes mellitus (p < 0.001)
≥ 10; Prevalence: 23.2% Parity 2-4; Prevalence: 1.2%
Score: 15 Selected at high level hospital; no adjustments
Lauszus et al. 46
(Denmark/1999)
Cohort 383 Secondary
75g/3hs Age; weight; prior BMI; height, parity; gestational age
Incidence: 14% Association: > age, > BMI
> parity, < weight gain > gestational diabetes mellitus risk
Score: 17 Screening for risk factors; no
adjustments
Moses et al. 18
(Australia/1999)
Case-control 276 Secondary
Third trimester 75g/2hs
ADIPS
Mother’s pregnant age at birth, gestational age,
birth weight; length
No association for birth weight Score: 10 Cases: referred to
treat gestational diabetes mellitus,
born in hospital that attended 50% of births. Controls: next baby born same hospital same
gestational age, mother’s age (± 2 years) to the pregnant
mother case; only collected birth weight;
no adjustments
Pettitt et al. 17
(USA/1998)
Cohort 831 Primary
75g/2hs WHO
Birth weight, age, weight, height, BMI, family history of diabetes
mellitus
Adjusted association: < birth weight > gestational diabetes
mellitus risk
Score: 16 Do not shows analysis
Plante et al. 15
(USA/1998)
Cohort 6,550 Secondary
Medical record Birth weight, gestational age, race (white, black)
Prevalence: 1.5% Association: whites with small for gestational age > gestational
diabetes mellitus risk
Score: 17 No differentiation
among previous diabetes mellitus or gestational diabetes mellitus; did not separate large for
gestational age from adequate for gestational age; no
adjustments
Plante et al. 16
(USA/2002)
Cohort 7,802 Secondary
Medical record Birth weight, gestational age, race (white, black)
Prevalence: 2.9% No association for birth weight
Score: 17 Same population of the previous study < prevalence of small for
gestational age Table 1 (continued)
(continues)
Authors
(place/year) Designn Data source
Gestational time Gram glucose/
time diagnostic
criteria
Risk factors
investigated Prevalence/Association with Main results gestational diabetes mellitus
Rao et al. 49
(USA/2006)
Cohort 3,779 Secondary
No information Age, education, parity, prenatal, insurance,
hypertension
Adjusted association: Indian-Pakistanis > gestational diabetes
mellitus risk Score: 18 Comparisons between seven self-referred ethnic groups: American-Asians, Islands of the Pacifi c,
against the total prevalence of this sample; European white was not included; data of one
hospital
Rao et al. 49
(USA/2006)
Cohort 6,511 Secondary
No information Age, education, parity, obesity, insurance, hypertension, multiple pregnancy, gestational
diabetes mellitus
Adjusted association: Chinese and Philippines > gestational diabetes mellitus risk regarding
Japanese
Score: 16 Ethnicity designated
and gestational diabetes mellitus
self-referred; comparison between ethnicities
Rodrigues et al. 53
(Canada/1999) Cohort 402/7,718 Secondary 24-30 weeks 100g/3hs NDDG
Age, ethnicity, weight gain, height, parity, smoking habits, physical
activity
Prevalence of Canadian natives: 11.4%; Adjusted association: >
age, prior weight Prevalence of non natives: 5.3%;
adjusted association: > age,> parity, > weight, smoking habits,
< height
Grouped regression: interaction ethnicity vs. weight: obese natives 2x > risk of gestational diabetes mellitus compared to
obese non natives
Score: 19 Comparison risk factors gestational diabetes mellitus in native-Canadians cohort vs. risk factor gestational diabetes mellitus non-native Canadians; lack of information for height
Rudra et al. 28
(USA/2006) Cohort 1,644 Primary 24-28 weeks 100g/3hs NDDG Age, race/ethnicity, family history of diabetes
mellitus, education, job, income, physical activity, smoking habits, weight
change, height, prior BMI, parity
Adjusted association: < height, > prior BMI, weight increase
after 18 years > gestational diabetes mellitus risk
Score: 20 One hospital
Rudra et al. 73
(USA/2006)
Case control; cohort 216 cases; 472 control; cohort: 897
Primary/Secondary 24-28 weeks 100g/3hs NDDG Age, race/ethnicity, hypertension; prior BMI, parity, physical activity (type, frequency,
duration year before)
Adjusted association: < insertion physical activity; < metabolic equivalent hours/weeks physical
activity > gestational diabetes mellitus risk
Score: 18 (case-control)/Score: 19
(cohort) Recreational physical
activity self-referred year before; refuse: 83% (cases)/58%
(controls)
Saldana et al. 60
(USA/2006) Cohort 952 Primary 24-29 weeks 100g/3hs Carpenter & Coustan
Age, height, weight; prior BMI, weight gain
Adjusted association: > weight gain, > prior BMI > gestational
diabetes mellitus risk
Score: 20 Sample: 57% eligible
pregnant
Savona-Ventura & Chircop 23
(Malta/2003) Case-control 162/250 Primary/Secondary 75g/2h > 155mg/dL
Birth weight; family history of diabetes
mellitus
Association: low and high birth weight, motherhood history of diabetes mellitus > gestational
diabetes mellitus risk
Score: 17 Cases: gestational diabetes mellitus; control general population same period No reference regarding diagnosis of gestational diabetes mellitus; non
adjustments
Seghieri et al. 22
(Italy/2002) Cohort 604 Primary/Secondary 24-28 weeks 100g/3hs ADA
Birth weight, age, parity, family history of diabetes mellitus, weight; BMI
(prior; current)
Adjusted association: > age, family history of diabetes mellitus, low birth weight > gestational diabetes mellitus risk
Score: 17 Pregnant with risk factors, weight and
birth self-referred Table 1 (continued)
(continues)
Authors
(place/year) Designn Data source Gestational time Gram glucose/ time diagnostic criteria Risk factors
investigated Prevalence/Association with Main results gestational diabetes mellitus
Solomon et al. 42
(USA/1997)
Cohort 14,613 primary
Self-referred Age, race/ethnicity, family history of diabetes
mellitus, height, prior BMI; BMI at 18 years, weight increase, smoking habits, physical
activity
Incidence: 4.9% Adjusted association: > age, non whites, family history of diabetes mellitus, > prior BMI, BMI at 18 years, weight gain, smoking
habits, > vigorous physical activity > gestational diabetes
mellitus risk
Score: 20 Self-referred gestational diabetes
mellitus, weight, height
Tabak et al. 31
(Hungary/2002) Cohort 1,635 Primary 75g WHO
Weight, height, BMI, age, education, family
history of diabetes mellitus
Prevalence: 5.7% Association: > BMI, > age, > family history of diabetes mellitus > gestational diabetes
mellitus risk
Letter to editor without evaluation
Terry et al. 44
(Sweden/2003) Cohort 212,190 Secondary Handbook register ICD 9th revision
Age, weight, height, BMI, smoking habits,
living with father
Prevalence: 0.4% Association: > age, < height > BMI, stop smoking between
gestations > gestational diabetes mellitus risk Adjusted association: > BMI, <
education, > age
Score: 13 Different criteria
for diagnosis of gestational diabetes
mellitus
Thorsdottir et al. 64
(Iceland/2002) Cohort 615 Primary 75g/2hs WHO
Age, height, marital status, smoking habits, parity, weight gain, prior
weight, hypertension, prior eclampsia
Association: < weight gain > gestational diabetes mellitus risk
Score: 20 Sample size to other
variables, not to gestational diabetes mellitus. Gestational diabetes mellitus. Weight gain at the
end of pregnancy
Williams et al. 19
(USA/1999) Cohort 41,839 Secondary Self-referred/ Medical record ICD 9th revision
Age, marital status, education, health system, parity, prior weight , weight gain,
smoking habits, prenatal, hypertension
Non-Hispanic whites = 2.8%; Afro-Americans: 2.6%; Native-Americans: 2.7%; Hispanics:
3.0%
Adjusted association: low birth weight for all ethnic > gestational diabetes mellitus risk
Score: 19 Secondary data; with self-referred gestational diabetes mellitus; links between
data banks 88.8% of pregnant women
Yang et al. 29
(China/2002) Cohort 9,471 Primary 26-30 weeks 75g/2hs WHO
Age, home income, education, height, weight gain, prior BMI, family history of diabetes
mellitus, abortion, smoking habits, previous
illnesses, alcohol
Prevalence: 2.31% Adjusted association: > age, <
height, > prior BMI, smoking habits, family history of diabetes mellitus, weight gain > gestational diabetes mellitus risk
Score: 17 Weight gain was associated only at
adjusted analysis
Yue et al. 47
(Australia/1996) Cohort, 3,807 Primary 24-28 weeks 75g/2hs ADIPS
Age, ethnicity, BMI, parity
Prevalence: 6.7% Adjusted analysis for age and BMI: Chinese OR 5.6; Vietnams
OR 3.6; Indians OR 6.4; Arabs OR 2.5, Aborigines OR 3.7 regarding the Anglo-Celtics
Score: 18 Data collected at
a prenatal clinic. Exclusion of 24% of data because belonging to 30 different races
Zhang et al. 74
(USA/2006)
Cohort 21,765 Primary
Self referred Age, race, family history of diabetes mellitus, weight, BMI, smoking habits, parity, prior physical activity, diet,
alcohol
Incidence: 6.5% Adjusted association: > physical
activity, > metabolic equivalent hours/weeks; walking fast or very
fast, to go up stairs (≥ 15 steps/ day); less time watching TV < gestational diabetes mellitus risk
Score: 20 Physical activity
measured questionnaire vs. one record week , correlation: 0.79
ADA: American Diabetes Association; ADIPS: Australasian Diabetes in Pregnancy Society; BMI: Body Mass Index; DIAGEST: Study Group on Gestational Diabetes; ICD: International Classifi cation Diseases; NDDG: National Diabetes Data Group; WHO: World Health Organization.
Table 1 (continued)
Authors
(place/year) Designn Data source Gestational time Gram glucose/ time diagnostic criteria Risk factors
investigated Prevalence/Association with Main results gestational diabetes mellitus
tion between birth weight and delayed risk of type 2 diabetes mellitus 11,12,13, insulin resistance 12,14 and other factors of metabolic syndrome
11,12,14.
Ten studies that evaluated such an associa-tion were identified. Plante 15, in 1998, found
that women who were born “small for the ges-tational age” presented a fourfold risk of gesta-tional diabetes mellitus. However, when analyz-ing the same cohort four years later (at the ages of 24 to 26), using the same methodology, they did not find statistical significance, although they did identify an inverse trend in the rela-tionship between birth weight and gestational diabetes mellitus. In the second sample, there was a smaller number of pregnant women that had been born small for the gestational age 16.
In both analyses, the authors had not adjusted for family history of diabetes mellitus, nor had separated the mothers who had been born with adequate weight from the ones that had been born large for gestational age. Large babies at birth, children of mothers with diabetes mellitus or gestational diabetes mellitus that were part of the comparison group, could dilute the effect of the association between low birth weight and gestational diabetes mellitus. Studies carried out with the Pima Indians from Arizona, United States 17, had shown a “U-shaped” association,
small for the gestational age and large for gesta-tional age women presented an increased risk of diabetes mellitus, but after controlling for family history of diabetes mellitus the association was no longer significant.
In 1999, a small Australian study by Moses et al. 18, examining pregnant women referred for
medical management of their gestational dia-betes mellitus, found that the mean 2-h glucose concentration at diagnosis of gestational diabe-tes mellitus presented a U-shaped association when women with gestational diabetes mellitus had been analyzed apart as three groups – small for gestational age, adequate for gestational age and large for gestational age. Among women di-agnosed with gestational diabetes mellitus, the 2-h glucose level was higher among the small for gestational age group than in the adequate for gestational age group, which could suggest a higher insulin resistance between the small for gestational age women, however the association was not statistically significant. In the same year, Williams et al. 19, in a large study of pregnant
women divided into four racial groups, (white non-Hispanic, Afro-American, Hispanic and Na-tive-American) found twofold risks in the asso-ciation between < 2,000g birth weight and gesta-tional diabetes mellitus, for all groups, compared to 3,000-3,999g, even after adjustment for age,
parity, marital status, health insurance, cigarette smoking and arterial hypertension, although in some categories, because of the small number of gestational diabetes mellitus, the association was not significant.
In 2000, Egeland et al. 20 studied a large
ret-rospective cohort in Norway (138,714 pregnant women) and identified an inverse trend of ges-tational diabetes mellitus with birth weight and weight for gestational age (OR: 1.8; 95%CI: 1.1-3.0; and OR: 1.7; 95%CI: 1.2-2.5, respectively). The comparison was done between women with birth weight < 2,500g, compared to those weigh-ing 4,000-4,500g as a reference group. The analy-ses were controlled for age, parity and history of diabetes mellitus of the mother of the pregnant woman.
Later in 2002, Innes et al. 21 carried out a study
enrolling 23,395 pregnant women that were born in New York State in the Unites States. The ad-justed analyses had strengthened the inverse dose-response relationship and the magnitude of the association between low birth weight and the risk of gestational diabetes mellitus between women born weighing less than 2,000g (OR: 4.23; 95%CI: 1.55-11.51) in relation to those born with 3,500-3,999g. The inverse association between birth weight and gestational diabetes mellitus was strong for women that were born preterm and those born at term. The adjusted analyses included age, primiparity, twins, and maternal complications of pregnancy during her own in-trauterine life, such as preeclampsia/eclampsia and diabetes mellitus of her mother. Regarding the current pregnancy, the authors adjusted for socioeconomic and demographic variables (age, race, education, and occupation), height, pre-pregnancy body mass index (BMI) and weight gain.
In 2002, in Italy, Seghieri et al. 22 found a
significant association between birth weight < 2,600g and gestational diabetes mellitus after adjustment for age, parity, family history of dia-betes mellitus and pre-pregnancy BMI. The odds ratio to present gestational diabetes mellitus was nearly two times higher among women with birth weight < 2,600g, when compared to higher birth weights (OR: 1.89; 95%CI: 1.09-3.29).
A small study on the island of Malta 23, with
Figure 1
Low birth weight Funnel plot.
Funnel plot with pseudo 95% confidence limits
0
0.1
0.2
0.3
Standar
d err
or
1 2 3 4 5 log OR
association found between large for gestational age and gestational diabetes mellitus occurred particularly between women with a family his-tory of diabetes mellitus and, especially, among those with maternal history of diabetes mellitus.
In Italy in 2003, Bo et al. 24, found that
glu-cose tolerance decreases according to weight quartiles: 3,389±644; 3,184±583 and 3,077±661 respectively for normoglycemic, glucose intoler-ant and gestational diabetes mellitus pregnintoler-ant women. When the analysis excluded pregnant women born to gestational diabetes mellitus mothers, a mean weight decrease was observed in all categories and among the gestational diabetes mellitus women the birth weight was 2,992±581 on average. When controlling for age, gestational age, maternal diabetes, pre-pregnan-cy BMI and weight gain, the OR were 3.7 (95%CI: 1.72-8.00).
The funnel plot (Figure 1) does not show evi-dence of publication bias. Conclusions from the available studies point out the importance of adjusting birth weight for family history of dia-betes mellitus and especially for maternal diabe-tes mellitus, since the daughters of women who present gestational diabetes mellitus have great-er risk to present high birth weights and strong
genetic and/or environmental characteristics that increase the chance for gestational diabe-tes mellitus in their pregnancy. In this way, when comparing mean birth weight of mothers with and without gestational diabetes mellitus, those who were heavier at birth are probably born from mothers who also had gestational diabetes mel-litus. This fact will increase the mean birth weight among mothers at increased risk from genetic basis. On the other hand, when birth weight is analyzed as a dichotomous variable (low birth weight – yes/no), the normal weight category would include macrossomic babies. In these two situations if there is no control for maternal diabetes, the potential association between low birth weight and gestational diabetes mellitus may not be detected.
As for the control of birth weight for gesta-tional age, although it does not seem to change the association 20,21, there is still no strong
evi-dence to simply ignore such an adjustment.
Height
a cohort of Korean women, found that the height of pregnant women, divided into quartiles, was inversely associated with the gestational diabe-tes mellitus diagnosis. The association remained regardless of age, weight and pre-pregnancy BMI, family history of diabetes mellitus, parity and weight gain during pregnancy. Anastasiou et al. 26, evaluating a cohort of pregnant Greek
women referred to a service for screening of dia-betes, found that the mean height among preg-nant women with gestational diabetes mellitus was significantly lower than among those with-out gestational diabetes mellitus. Such findings remained true even after stratification by weight, maternal schooling and cohort effect. Branchtein et al. 27, in 2000 in Brazil, found an inverse
asso-ciation between mean glycemic values one and two hours after glucose load and height. Logistic regression showed that shorter women (≤ 151cm) had a 60% greater increase (OR) of gestational diabetes mellitus, when compared with the ones from the highest quartile, independently of the prenatal clinic of origin, age, obesity, family his-tory of diabetes mellitus, education, skin color, waist circumference, parity, previous gestational diabetes mellitus, environment temperature and gestational age. Rudra et al. 28, in 2006, studying
an American cohort found significant associa-tion between height (in quartiles) and gestaassocia-tion- gestation-al diabetes mellitus. Adjusted angestation-alyses for age, race/ethnics, education and BMI had shown that heights above 160cm were protective (30-60% risk reduction) for the development of the dis-ease.
Other studies evaluating the association be-tween height and gestational diabetes mellitus presented conflicting results: Yang et al. 29 in 2002,
investigated height averages of diabetic and non diabetic pregnant Chinese women; Iranians were studied by Keshavarz et al. 30 in 2005; and Tabak
et al. 31 assessed pregnant Hungarians in 2003
but did not find significant differences in a com-parison of mean values. Only the first study con-trolled for confounders 29. The findings among
different ethnicities was discussed by Kousta et al. 32, in 2000, studying mean differences,
com-paring pregnant women with and without ges-tational diabetes mellitus, categorized by origin as European, South Asian and Afro-Caribbean. Short stature associated to gestational diabetes mellitus had been found for all the groups in the crude analysis, although the association between Afro-Caribbean was not statistically significant
32. On the other hand, studying several risks for
the development of gestational diabetes mellitus, Di Cianni et al. 33 and Innes et al. 21, respectively,
in Italian and American populations, had also found a significant inverse association between
height and gestational diabetes mellitus, even af-ter adjustments for confounders.
Genetic and hormonal factors apart, fetal and infant nutrition are important determinants of height in adulthood 34. Therefore, the association
between short stature and gestational diabetes mellitus could in fact be a result of confounders such as low socioeconomic level, and to be medi-ated by obesity. That could also be explained by the fetal origin theory. Considering that insulin is an important factor for normal growth, directly or indirectly (through GH/IGF1 axis), short stat-ure would only be a marker of insulin resistance. It is important to point out that for this potential risk factor publication bias cannot be ruled out as shown in the funnel plot (Figure 2).
Socioeconomic level/education
Considering socioeconomic levels, Innes et al. 21
did not find an association between gestational diabetes mellitus development and private or public insurance, occupation during pregnancy, or education of the parents of the pregnant wom-an at the time of her birth. However, they found an inverse association between the educational level of the pregnant woman and gestational dia-betes mellitus, after adjustment for other social, economic and demographic factors. Berkowitz et al. 35, studying a hospital sample composed of all
socioeconomic categories, found greater preva-lence of gestational diabetes mellitus among women in a public health service, compared with those coming from private clinics 35. A study
car-ried out in Italy 24 found that high levels of
ma-ternal education were associated with reduced risks of gestational diabetes mellitus (OR: 0.61; 95%CI: 0.4-0.9), compared to less educated wom-en. When categorized by occupation, non-em-ployed women with a primary level of education presented an OR of 1.87 (95%CI: 1.1-3.2) and the blue-collar workers, an OR of 1.73 (95%CI: 1.1-2.9), compared to white-collar women, even after controlling for age, BMI, height, family history of diabetes mellitus and previous pregnancy 24. On
the other hand, Yang et al. 29, when studying
Chi-nese pregnant women, did not find an associa-tion between gestaassocia-tional diabetes mellitus and education or average household income. Kesha-varz et al. 30, studying pregnant Iranian women,
did not find an association between gestational diabetes mellitus and education or occupation; however, they did find an association with low socioeconomic level. Both studies did not con-trol for confounders.
Figure 2
Height Funnel plot.
Funnel plot with pseudo 95% confidence limits
0
0.5
1
1.5
Standar
d err
or
log OR
20 40 60
the epidemiologies of these two conditions are similar, it is not clear if the socioeconomic situ-ation can be a risk factor for gestsitu-ational diabe-tes mellitus. It is possible that the low maternal socioeconomic level is a proxy for the socio-economic level of the parents, and the latter is potentially acting as a confounding factor for being born with low weight, short stature and greater weight in adulthood, characteristics that, in previous studies, had been detected as more frequent in poor populations and with smaller education levels and described as independent factors of type 2 diabetes mellitus risk. Thus, a careful hierarchical analysis taking into account the income of the parents could elucidate the re-lationship between current socioeconomic fac-tors and gestational diabetes mellitus 38.
Cigarette smoking
Although cigarette smoking is positively associ-ated with hyperinsulinism and insulin resistance in some studies 39,40, the association between
to-bacco and gestational diabetes mellitus has been little investigated. A cross-sectional study carried out in Scandinavia 41 showed that to smoke more
fects the homeostasis of the glucose towards ges-tational diabetes mellitus, which was confirmed by others 42. In the Nurse Cohort study 42, in the
study by England et al. 43, and in another cohort
of Chinese pregnant women 29, an increased
risk for gestational diabetes mellitus was found among smokers compared to non smokers. In the first cohort, the gestational diabetes melli-tus diagnosis was self-reported and the defini-tion of smoking habits consisted of pre-gravid current smokers. In the others, the gestational diabetes mellitus diagnosis was made by means of an oral glucose tolerance test and cigarette smoking during pregnancy in the first was cat-egorized as never smoked, quit before, quit dur-ing and smoke at enrollment and in the Yang et al. 29 study as non smoker (none or occasional)
or smoker (to smoke one or more cigarettes per day). Although adjustments were carried out for the same confounders, Yang et al. 29 found higher
al. suggests a lack of precision in the estimate, since only two of the diabetic pregnant women were smokers 29,42.
Other studies have not found this association
21,35,44. Berkowitz et al. 35 did not include cigarette
smoking in the multivariate analysis and, there-fore, had not adjusted its effect for the effects of other variables; and Innes et al. 21 and Terry et al. 44
carried out studies with young pregnant women, with average ages of 21 and 24 respectively, prob-ably with less time of exposure to smoking. One methodological problem of the studies was that some studies 21,29,35 classified women as smokers
(at least one cigarette per day) or non-smokers, without considering the exposure period.
Parity
In the study by Egeland et al. 20 2000, after
con-trolling for age, they found an OR for women with two, three and four or more childbirths, compared to those with only one childbirth, of respectively, 1.5 (95%CI: 1.2-1.9), 1.9 (95%CI: 1.4-2.5) and 3.3 (95%CI: 2.1-5.1). Kumari et al. 45 2002,
studying grand multiparity, in a uniformly high socioeconomic population (United Arab Emir-ates), found that women with parity ≥ 10 had greater gestational diabetes mellitus incidence. When stratified by age, these pregnant women belonged to the oldest category.
Jang et al. 25 1998 and Di Cianni et al. 33 2003
found greater ratio of women with gestational diabetes mellitus in the group with parity ≥ 2, in comparison to primiparas. After controlling for age, pre-pregnancy BMI, height, family history of diabetes mellitus and weight gain during preg-nancy, both results were non statistically signifi-cant.
For Berkowitz et al. 35 1992, in the crude
analysis, the prevalence of gestational diabetes mellitus increased with parity, relative risks for two, three and more than four children, in re-lation to the first pregnancy, respectively 1.14 (95%CI: 0.88-1.50), 1.71 (95%CI: 1.25-2.34) and 2.17 (95%CI: 1.57-3.00). Lauszus et al. 46 1999 and
Keshavarz et al. 30, in a descriptive analysis, found
that women with more children were more likely to present gestational diabetes mellitus.
The association between parity and diabe-tes is strongly linked to obesity and age. Women with higher parity frequently are older and more obese. Obesity is an intermediate outcome in the causal pathway between parity and gestational diabetes mellitus, probably a mediating factor. However, age is a potential confounder in the as-sociation between parity and gestational diabe-tes mellitus. Therefore, no study evaluating par-ity could ignore to control for age. Adjustments
for BMI, on the other hand could diminish the strength of this association. To study this associa-tion through a hierarchical model could provide a better estimate of the association between great-est parity and the risk of developing ggreat-estational diabetes mellitus.
Race, ethnicity
The observation that some racial and ethnic groups presented higher gestational diabetes mellitus frequencies have stimulated studies to evaluate the role of racial or ethnic factors. A study carried out by Berkowitz et al. 35, in 1992,
raises a controversy in relation to the risk of ges-tational diabetes mellitus based on habits and behavior changes of immigrant populations. In a cohort of pregnant women from different so-cioeconomic and ethnics backgrounds in New York, the authors found a higher adjusted risk of gestational diabetes mellitus for Orientals, women from India, the Middle East and among Hispanics (only those born outside the USA). A study carried out in Australia, in 1996, strength-ens these findings, showing that gestational diabetes mellitus is more common among im-migrant populaces, especially among minorities (racial groups), even after adjustment for age and BMI 47.
Another study 48, in the USA, investigated the
impact of the birth on the prevalence of gesta-tional diabetes mellitus, between 15 ethnic and racial groups (among them native, Hispanic, non Hispanic whites, Afro-descendants and Asians). Having been born outside the USA and having immigrated increased the probability of having gestational diabetes mellitus. In part, this asso-ciation was explained by the age of the mother, as the oldest pregnant women were immigrants. The significant association between several racial and ethnic groups remained the same even after controlling for age. The authors, however, had not adjusted for important confounders such as socioeconomic and obesity variables. This study also demonstrated that Japanese women born outside the USA have the lowest prevalence of gestational diabetes mellitus with adjusted OR (0.74; 95%CI: 0.69-0.81) compared to non His-panic white women born in the USA. This finding was confirmed by Rao et al. 49, suggesting that
and even greater than those who are residents of Japan 50.
Dornhorst et al. 51, in London, found ethnic
origin to be a stronger predictor of gestational diabetes mellitus than age, BMI or parity, and a similar result was also found by Khine et al. 52
among pregnant American women, when they evaluated prevalence of gestational diabetes mellitus stratified by race and age. Clear racial differences had also been found in the study of nurses, in which women who were Afro-Ameri-can, Hispanic or that had Asian ethnicity had a significantly increased risk of gestational diabe-tes mellitus, when compared with whidiabe-tes, even after adjustment for BMI, age, family history of diabetes mellitus, level of physical activity and parity. Being this study made in cohort of women of same professional category, there was, in a cer-tain way, an adjustment for restriction, to social and economic factors 42.
On the other hand, Innes et al. 21, when
study-ing pregnant women in the state of New York in 2002, did not find an association between ges-tational diabetes mellitus and race when the sample was divided into groups of “non-Hispan-ic whites”, “black people” “Hispan“non-Hispan-ic” and “other non-whites”.
Studies have also been carried out with native populations (Cree) from Canada. The increased risk was only found among obese natives in com-parison to non native Canadians 53.
Funnel plots suggest that the risks found for Asians are not a result of publication bias (Figure 3), while those associated with Indians/Pakistan-is may be biased. It Indians/Pakistan-is interesting to note that the highest prevalence of gestational diabetes mel-litus found among ethnic groups was observed in studies carried out with populations of immi-grants in Western countries. In studies made in the original populations, the prevalence is lower than in Western countries 29,54,55. It is important to
point out that more recent studies show that the prevalence of diabetes mellitus is increasing in China and in other Eastern countries, due to ad-aptations to modern lifestyles, brought about by the economic developments of the last decade 56.
Far beyond genetic questions and change in lifestyle, aspects linked to prejudice must also be considered. Emotional stress can influence metabolic functions, because it increases the production of cortisol and other hyperglycemic hormones, besides activating the pro-inflamma-tory elements of the innate immune system and modifying the sympathetic nervous system 57.
Figure 3
Asian ethnic Funnel plot.
Funnel plot with pseudo 95% confidence limits
0
0.1
0.2
0.3
0.4
Standar
d err
or
log OR
Thus, in developed countries, the highest risk of diabetes mellitus and gestational diabetes mel-litus, between different ethnic groups, could be justified by genetics, age of pregnant immigrant, by lifestyle changes, socioeconomic factors and, possibly, as a result of suffering prejudice.
Weight gain
The Brazilian Society of Diabetes (SBD) consid-ers as a risk factor for gestational diabetes mel-litus excessive weight gain 58, however few
stud-ies evaluated this variable as an independent risk factor.
One of the first studies was published by Scholl et al. 59, in 1995, among low income
preg-nant and racial minorities from New Jersey, USA. The authors showed that high concentra-tions of insulin were associated with a greater increase and retention of weight post-partum. Later, studies by Jang et al. 25, in 1998, Yang et
al. 29, 2002 and Saldana et al. 60, 2006 controlling
for age, weight and pre-pregnancy BMI, height, family history of diabetes mellitus and parity, have shown a significant association between weight gain and gestational diabetes mellitus, some studies have also adjusted for smoking habits and alcohol use.
Saldana et al. 60, also evaluated the
associa-tion between weight gain at the end of the sec-ond semester (and the US Institute of Medicine weight gain recommendation 61) and the risk
of glucose intolerance and gestational diabetes mellitus, finding higher risks than in the previous analyses. A high statistical significance (< 0.0001) was also found in an adjusted analysis in the dif-ference between weight gain among pregnant women with gestational diabetes mellitus or not, at the moment of the diagnosis, in the study of Di Cianni et al. 33.
On the other hand, in a Letter to the Editor, Corrado et al. 62 stated that in a retrospective
study in Italy they did not find an association be-tween gestational diabetes mellitus and weight increase. This was also true for Deruelle et al. 63,
in 2004, who compared weight gains above 18kg to lower gains. And in another study, women with BMI ranging from 19.5 to 25.5kg/m2 gaining less
than 11kg during pregnancy were more likely to present gestational diabetes mellitus in compari-son to those gaining more than 20kg (p = 0,02) in the crude analysis of the study by Thorsdottir et al. 64, however the sample was too small to study
the outcome. These findings were confirmed by Innes et al. 21, analyzing weight gain in quartiles
(< 11.35; 11.35-15.8; 15.9-20.4 and 20.5kg), and observing a crude OR for gestational diabetes mellitus that was smaller for pregnant women
in the highest quartile of weight gain, without statistical significance after adjustments (also for pre-pregnancy weight); and by Lauszus et al. 46,
comparing average weight gain in women with a normal oral glucose tolerance test and diabetic women. As obesity is a known risk factor for ges-tational diabetes mellitus, it is possible that the effect of this variable was biased by reverse cau-sality, since high-weight pregnant women with other risk factors for gestational diabetes mellitus are oriented not to gain weight during pregnancy. The differences in the results might also be ex-plained by the time interval in which weight gain was measured: in the four first studies, weight gain was measured up until the gestational dia-betes mellitus diagnostic test, while other studies measured up until the end of the pregnancy. Be-havioral changes, indicated for the treatment of gestational diabetes mellitus could have an influ-ence on weight increase after the diagnosis.
Physical activity
Physical activity has been associated to a reduced risk for excessive weight gain, insulin resistance and type 2 diabetes mellitus 65,66,67. Few studies
evaluated the association between physical ac-tivity and gestational diabetes mellitus, however it has been stated that increasing physical activ-ity could decrease the glucose intolerance in dia-betic pregnant women 68.
The lack of studies can be attributed, in part, to the difficulty in measuring this variable, the potential reverse causality and recall biases, as well as poor prenatal care counseling towards physical activity.
In 1997, Solomon et al. 42 measured
pre-pregnancy physical activity, in terms of mean metabolic equivalent expenditures 69. This study
found a non significant reduction of gestational diabetes mellitus risk for women who were vigor-ously physical active or did brisk walking before pregnancy. Dye et al. 70, also in 1997, found that
inactive women presented OR: 1.9 (95%CI: 1.2-3.1) for gestational diabetes mellitus, compared to active women, only among those with BMI pre-pregnancy > 33. This study considered as physical activity those activities performed dur-ing leisure time.
Dempsey et al. 71,72, in a case-control study
al. 28,73 in a case-control study and as a cohort,
as-sessing the relation between perceived exertion during pre-pregnancy recreational physical ac-tivity, divided in weak, moderate, strenuous and very strenuous and gestational diabetes mellitus. The reduced risk for gestational diabetes mel-litus was 59% for moderate, up to 81% for very strenuous, in relation to weak, in the case-control study, and 37% and 43%, respectively, in the co-hort study.
A recent study with the population from the Nurse’s Health Study II, observed an adjusted risk ratio of the comparison between the highest and the lowest quintile of vigorous activity, equal to 0.77 (95%CI: 0.69-0.94). Still, among women who have not performed vigorous activities, brisk walking and climbing stairs (up to 15 steps daily) were associated with risk reduction 74. In spite
of different ways of measuring physical activity, studies highlight the importance of this variable as an independent protective factor for gesta-tional diabetes mellitus.
Conclusions
The systematic review of the literature allows us to draw the following conclusions:
(a) Well designed studies 20,21, found
in-creased risks in the association between low birth weight and gestational diabetes mellitus. Some studies found there to be a statistical significance although with no control for family history of diabetes mellitus and BMI 19 and with no weight
categorization 15, which guaranteed significance
for others 23. According to the literature,
mater-nal history of low birth weight must be included as a risk factor for gestational diabetes mellitus. New studies must either consider controlling for familiar history of gestational diabetes mellitus (mainly the mother of the pregnant woman) or always separate birth weight categories that con-template the highest weights separately in order to investigate this association;
(b) In relation to height, all but one of the studies found an association. Although publica-tion bias cannot be ruled out, the challenge in including short stature as a risk factor for gesta-tional diabetes mellitus seems to be the defini-tion of the cut-off point for this variable. In Bra-zil, based on the Brazilian Gestational Diabetes Study (EBDG), the study of Branchtein et al. 27
defined it as ≤ 151cm, however studies in other countries observed associations using different height categories 21,25,26,29,33.
(c) Socioeconomic levels are investigated mostly in studies carried out in developed
coun-ing countries hinder comparison with developed countries. Due to controversial results, it could be more elucidative to study this association in countries where differences between high and low socioeconomic levels are huge, and there-fore, the potential association would be more easily proven;
(d) Regarding smoking habits, half of the studies found there to be a statistically signifi-cant association. These differences in the results may result from a lack of power, different smok-ing exposure measurements, differences in the diagnostic methods, different definitions of the exposure, besides different confounders’ con-trol. Changes in smoking habit as a result of the pregnancy or wrong information about smoking status (since risks associated to tobacco expo-sure in pregnancy are well known), also could be sources of bias. The heterogeneity of the studied populations, the lack of control, in some cases, for known potential confounding factors and the effect of others, still not described, may also have led to different results. In order to clarify this association, more studies are necessary, with sample sizes large enough to contemplate the possible confounding factors and standardiza-tion of exposure;
(e) The association between parity and dia-betes seems consistent in the different studies investigated and is marked by a dose-response fashion. However, women with highest parity are frequently older and heavier. Therefore, no study that evaluates parity could ignore a proper age adjustment. In the evaluated studies, only two had adjusted for age, presenting conflicting re-sults. To identify the mediating effect of obesity, hierarchical analyses could show the real asso-ciation between high parity and the risk of devel-oping gestational diabetes mellitus;
(f) The racial question has not yet been well elucidated. Differences in the metabolic suscep-tibility to diabetes mellitus can exist, but ambi-ent factors, due to behavioral changes (such as physical activity or nutritional patterns), or fac-tors linked to emotional stress, associated to the immigrant situation, to the socioeconomic con-dition, must be more investigated in future stud-ies, especially in developed countries;
(g) The results found for weight gain during pregnancy are controversial since well designed studies presented conflicting results. Maternal pre-pregnancy weight influences the weight gain in the course of pregnancy 60. Studies evaluating
ques-(h) There are indications, through three cross-sectional studies and one cohort study, that physical activity performed right before and during pregnancy could modify the risk of gesta-tional diabetes mellitus. Studies would have to be carried out in women before the gestational diabetes mellitus diagnosis, with the objective to prevent the reverse causality associated to be-havior changes after the diagnosis of gestational diabetes mellitus. All domains of physical activity should be assessed (leisure time, commuting and occupational).
Different methodologies used by the re-searchers to define the exposures and outcome did not allow for a meta-analysis to be carried out. Although the literature reviewed suggests
that the investigated characteristics are risk fac-tors for gestational diabetes mellitus, the pres-ence of publication bias i.e. the preferential pub-lication of researches that present positive results cannot be discarded for the majority of risk fac-tors. This finding prevents the recommendation of including these factors among those that point out women in higher risk of gestational diabetes mellitus. The standardization of the techniques and cutoff points for screening and diagnosis, besides adequate sample sizes, will allow future meta-analyses, which make possible the confir-mation or the removal of these new criteria from the list of the risk factors for gestational diabetes mellitus.
Resumo
Idade, obesidade e história familiar de diabetes são fatores de risco bem conhecidos para diabetes melli-tus gestacional. Outros são controversos. O objetivo desta revisão é encontrar evidências na literatura que justifiquem a inclusão dessas condições entre os fatores de risco. Bases de dados MEDLINE, Cochrane, LILACS e Organização Pan-Americana da Saúde fo-ram procuradas. A revisão incluiu artigos de 1992 a 2006. Palavras-chave foram usadas em combinação com diabetes mellitus gestacional separadamente e com cada um dos fatores de risco estudados. A quali-dade metodológica dos estudos incluídos foi medida, totalizando 41 estudos. A maioria dos trabalhos que investigaram história materna de baixo peso, baixa estatura e baixa atividade física encontrou associação positiva com diabetes mellitus gestacional. Baixo nível sócio-econômico, fumo durante a gestação, alta pari-dade, pertencer a minorias e excessivo ganho de peso apresentam resultados conflitantes. Padronização de técnicas, pontos de corte para rastreamento e diagnós-tico, assim como estudos envolvendo maiores amostras podem permitir futuras metanálises.
Diabetes Gestacional; Diabetes Mellitus; Fatores de Risco
Contributors
References
1. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its com-plications. Report of a WHO consultation. Geneva: World Health Organization; 1999.
2. American College of Obstetricians and Gynecolo-gist. Management of diabetics in pregnancy. Wash-ington DC: American College of Obstetricians and Gynecologist; 1994.
3. American Diabetes Association. Gestational dia-betes mellitus. Diadia-betes Care 2003; 26 Suppl 1: S103-5.
4. Metzger BE, Coustan DR. Summary and recom-mendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. Dia-betes Care 1998; 21 Suppl 2:B161-7.
5. The Expert Committee on the Diagnosis and Clas-sification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2000; 23 Suppl 1: S4-19.
6. World Health Organization. Screening for type 2 diabetes: report of World Health Organization and International Diabetes Federation Meeting. Gene-va: World Health Organization; 2003.
7. Reichelt AJ, Oppermann MLR, Schmidt MI. Reco-mendações da 2a Reunião do Grupo de Trabalho
em Diabetes e Gravidez. Arq Bras Endocrinol Me-tabol 2002; 46:574-81.
8. Ministério da Saúde. Assistência pré-natal: nor-mas e manuais técnicos. 3a Ed. Brasília: Ministério
da Saúde; 1998.
9. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998; 52:377-84.
10. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and car-diovascular disease in adult life. Lancet 1993; 341: 938-41.
11. Law CM. Fetal and infant influences on non-insu-lin-dependent diabetes mellitus (NIDDM). Diabet Med 1996; 13(9 Suppl 6):S49-52.
12. Phillips DI. Birth weight and the future develop-ment of diabetes. A review of the evidence. Diabe-tes Care 1998; 21 Suppl 2:B150-5.
13. Rich-Edwards JW, Colditz GA, Stampfer MJ, Wil-lett WC, Gillman MW, Hennekens CH, et al. Birth-weight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999; 130(4 Pt 1):278-84.
14. Mi J, Law C, Zhang KL, Osmond C, Stein C, Barker D. Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China. Ann Intern Med 2000; 132:253-60.
15. Plante LA. Small size at birth and later diabetic pregnancy. Obstet Gynecol 1998; 92:781-4. 16. Plante LA. Low birth weight may not predict
diabe-tes in pregnancy. Diabediabe-tes Care 2004; 27:1759-60. 17. Pettitt DJ, Knowler WC. Long-term effects of the
in-trauterine environment, birth weight, and breast-feeding in Pima Indians. Diabetes Care 1998; 21
18. Moses RG, Moses J, Knights S. Birth weight of women with gestational diabetes. Diabetes Care 1999; 22:1059-62.
19. Williams MA, Emanuel I, Kimpo C, Leisenring WM, Hale CB. A population-based cohort study of the relation between maternal birthweight and risk of gestational diabetes mellitus in four racial/eth-nic groups. Paediatr Perinat Epidemiol 1999; 13: 452-65.
20. Egeland GM, Skjaerven R, Irgens LM. Birth charac-teristics of women who develop gestational diabe-tes: population based study. BMJ 2000; 321:546-7. 21. Innes KE, Byers TE, Marshall JA, Baron A, Orleans
M, Hamman RF. Association of a woman’s own birth weight with subsequent risk for gestational diabetes. JAMA 2002; 287:2534-41.
22. Seghieri G, Anchini R, De Bellis A, Alviggi L, Fran-coni F, Breschi MC. Relationship between gesta-tional diabetes mellitus and low maternal birth weight. Diabetes Care 2002; 25:1761-5.
23. Savona-Ventura C, Chircop M. Birth weight influ-ence on the subsequent development of gestation-al diabetes mellitus. Acta Diabetol 2003; 40:101-4. 24. Bo S, Marchisio B, Volpiano M, Menato G, Pagano
G. Maternal low birth weight and gestational hy-perglycemia. Gynecol Endocrinol 2003; 17:133-6. 25. Jang HC, Min HK, Lee HK, Cho NH, Metzger BE.
Short stature in Korean women: a contribution to the multifactorial predisposition to gestational diabetes mellitus. Diabetologia 1998; 41:778-83. 26. Anastasiou E, Alevizaki M, Grigorakis SJ, Philippou
G, Kyprianou M, Souvatzoglou A. Decreased stat-ure in gestational diabetes mellitus. Diabetologia 1998; 41:997-1001.
27. Branchtein L, Schmidt MI, Matos MC, Yamashita T, Pousada JM, Duncan BB. Short stature and gesta-tional diabetes in Brazil. Brazilian Gestagesta-tional Dia-betes Study Group. Diabetologia 2000; 43:848-51. 28. Rudra CB, Sorensen TK, Leisenring WM, Dashow
E, Williams MA. Weight characteristics and height in relation to risk of gestational diabetes mellitus. Am J Epidemiol 2007; 165:302-8.
29. Yang X, Hsu-Hage B, Zhang H, Yu L, Dong L, Li J, et al. Gestational diabetes mellitus in women of sin-gle gravidity in Tianjin City, China. Diabetes Care 2002; 25:847-51.
30. Keshavarz M, Cheung NW, Babaee GR, Moghadam HK, Ajami ME, Shariati M. Gestational diabetes in Iran: incidence, risk factors and pregnancy out-comes. Diabetes Res Clin Pract 2005; 69:279-86. 31. Tabak AG, Kerenyi Z, Nagy E, Bosnyak Z, Madarasz
E, Tamas G. Height and gestational diabetes mel-litus. Diabet Med 2002; 19:344-5.
32. Kousta E, Lawrence NJ, Penny A, Millauer BA, Rob-inson S, Johnston DG, et al. Women with a history of gestational diabetes of European and South Asian origin are shorter than women with normal glucose tolerance in pregnancy. Diabet Med 2000; 17:792-7.
